MECHANISMS UNDERLYING THE NEUROPATHOLOGICAL CONSEQUENCES OF EPILEPTICACTIVITY IN THE RAT HIPPOCAMPUS IN-VITRO

Blockade of gamma-aminobutyric acid (GABA)ergic synaptic transmission in mature hippocampal slice cultures for a period of 3 days with convu lsants was shown previously to induce chronic epileptiform activity an d to mimic many of the degenerative changes observed in the hippocampi of epileptic humans. The cellular mechanisms underlying the induction of this degeneration were examined in the present study by comparing the effects of GABA blockers with the effects produced by the K+ chann el blocker tetraethylammonium (2 mM). Both types of convulsant caused a comparable decrease in the number of Nissl-stained pyramidal cells i n areas CA1 and CA3. No significant cell loss was induced by tetraethy lammonium when epileptiform discharge was reduced by simultaneous expo sure of cultures to tetrodotoxin (0.5 mu M) or to the anticonvulsants pentobarbital (50 mu M) or tiagabine (50 mu M). We conclude that this degeneration was mediated by convulsant-induced epileptiform discharge itself. The hypothesis that N-methyl-D-aspartate (NMDA) receptor-medi ated excitotoxicity underlies cell death in this model was tested by a pplying convulsants together with specific antagonists of glutamate re ceptors. Whereas coapplication of antagonists of both non-NMDA and NMD A receptors strongly reduced the degeneration induced by the convulsan ts, application of either class of antagonist alone did not. Applicati on of exogenous NMDA produced potent cell death, and this degeneration was blocked by the NMDA receptor antagonist yl-10,11-dihydro-5-H-dibe nzocyclohepten-5,10-imine (MK-801). Convulsants also induced a loss of dendritic spines that could be partially prevented by NMDA or non-NMD A receptor antagonists. We conclude that NMDA receptor activation is n ot solely responsible for the neuronal pathology resulting as a conseq uence of epileptiform discharge. (C) 1996 Wiley-Liss, Inc.